Managing Chronic Severe Hypertension in Pregnancy

A 30‐year‐old white woman with uncontrolled chronic hypertension was referred to the hypertension clinic on discovery of a positive pregnancy test. She was gravida 9 para 3 with 5 first‐trimester spontaneous abortions and had just completed an induced 34‐week delivery 6 weeks earlier. Her first and fourth pregnancies had come to term complicated by preeclampsia and gestational diabetes mellitus. Preeclampsia onset occurred at 29 weeks and 34 weeks. She was diagnosed with hypertension at age 20 years, but was poorly controlled on multiple antihypertensive agents over the past few years. A renal scan did not reveal obstructive flow, and 24‐hour urine collections for metanephrines and urinary free cortisol were normal. She had a 4‐year pregnancy hiatus, but following remarriage her most recent pregnancy was marked by severe hypertension and gestational diabetes. Systolic blood pressures (BPs) were 152–168 mm Hg and diastolic BPs were 112–128 mm Hg throughout this pregnancy. Her past medical therapy included an atrial ablation procedure for paroxysmal supraventricular tachyarrhythmia. She also had cluster headaches since childhood. She had a strongly positive family history of hypertension. Her mother had hypertension in her 20s and a stroke in her 40s. Her brother and sister both had hypertension in their 40s. During the recent brief postpartum interval, BPs were unchanged on hydrochlorothiazide 25 mg, metoprolol 100 mg bid, methyldopa 1000 mg bid, and hydralazine 100 mg bid.

On examination, the patient had normal weight, a BP of 172/122 mm Hg, and a heart rate of 108 bpm. Fundi and peripheral pulses were normal and the thyroid was not enlarged. There were no abdominal masses or bruits and no edema. The patient was seen every 1–2 weeks. Metoprolol was changed to labetalol, and calcium channel blockers were introduced. As her pregnancy progressed, she blamed methyldopa for a forearm dermatitis and felt better not taking it. Hydralazine was discontinued because of heart rates up to 128 bpm and palpitations. A workup for secondary etiologies of her hypertension (Table I) was negative and included normal magnetic resonance angiography of the renal arteries with and without gadolinium and normal magnetic resonance imaging of the kidneys and adrenal glands. Laboratory results included aldosterone level 39.0 ng/dL (normal, 3–34 ng/dL), renin 25.0 ng/mL/h (normal, 0.4–8.8 ng/mL/h), plasma norepinephrine 50 pg/mL (normal, 38–175 pg/mL), total plasma catecholamines 456 pg/mL (normal, <500 pg/mL), 24‐hour urine vanillylmandelic acid 4.1 mg/24 h (normal, <7 mg/24 h), total 24‐hour urine metanephrines 788 μg/24 h (normal, 95–475 μg/24 h), 24‐hour urine‐free cortisol 44 μg/24 h (normal, 20–90 μg/24 h), free thyroxine 0.74 ng/mL (normal, 0.7–1.48 ng/mL), and free triiodothyronine 312 pg/dL (normal, 200–380 pg/dL). The elevated renin and aldosterone levels were consistent with normal pregnancy; the elevated urine metanephrines level was attributed to artifact from concurrent labetalol. Assays of anticardiolipin antibody and lupus anticoagulant were normal.

Table I.

Tests Done to Rule Out Secondary Hypertension

Entity/Test
Renovascular hypertension
Renal artery magnetic resonance angiography
Hyperaldosteronism
Aldosterone and renin levels; adrenal magnetic resonance imaging
Pheochromocytoma
Plasma norepinephrine
Plasma catecholamines
24‐hour urine metanephrines
24‐hour urine vanillylmandelic acid
Cushing's syndrome
24‐hour urine free cortisol
Hyper‐/hypothyroidism
Free thyroxine, free triiodothyronine

Surveys of alanine aminotransferase, aspartate aminotransferase, and platelet counts were normal, and uric acid levels obtained every 2 weeks were 2.9–3.6 mg/dL (normal, 2.7–6.6 mg/dL).

Twenty‐four‐hour urine protein collections ranged from 113 to 150 mg/specimen (normal, <150 mg/specimen). Creatinine levels were 0.2–0.4 mg/dL (normal, 0.6–1.1 mg/dL). Frequent fetal monitoring over a 3‐month period showed normal vertex presentation with observed fetal body and limb movements and no placenta previa. Fetal growth was normal on serial examinations. BPs over the entire course of pregnancy were 162–196 mm Hg systolic and 112–134 mm Hg diastolic. The patient complained of intermittent headaches and palpitations, both of which were chronic. She had 2 overnight hospitalizations for palpitations associated with paroxysmal supraventricular tachyarrhythmia, but refused more prolonged hospitalization for BP control and signed out against medical advice on both occasions. At 30 weeks' gestation her BP was 172/124 mm Hg and heart rate 112 bpm on labetalol 400 mg bid, hydrochlorothiazide 25 mg daily, amlodipine 10 mg daily, and long‐acting diltiazem 360 mg daily. She appeared compliant with medication given her knowledge of her individual medications and the timing of refill pickups. At 31 weeks 5 days' gestation she was asymptomatic and admitted to the intensive care unit on a labetalol drip of 2 mg/h. Labor was induced, and the patient delivered a healthy child with birth weight appropriate for gestational age.

DISCUSSION

Managing hypertension in pregnancy often requires collaboration between the obstetrics service and specialists in clinical hypertension. Hypertension is the most common medical disorder of pregnancy, occurring in 10%–12% of pregnancies. ¹ Hypertension is a significant health care issue for 2 patients—the mother and the fetus. The trend toward pregnancy at later maternal age increases the prevalence of hypertension in pregnancy. According to 2000 National Health and Nutrition Examination Survey (NHANES) ³ data, the prevalence of hypertension in women aged 35–44 years was 18.6%, ² and there were 580,040 live births in women in this age group in 2004, compared with 366,190 births in this maternal age group during 1990.

This case discussion is best guided by addressing the following questions: What kind of pregnancy‐related hypertension did this patient have? How is superimposed preeclampsia diagnosed in a pregnant patient with chronic hypertension? What drugs are safe to treat chronic hypertension in pregnancy? What outcomes are expected with severe chronic hypertension of pregnancy? What are the indications for and considerations in early delivery?

What Kind of Pregnancy‐Related Hypertension Did This Patient Have? The most recent report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy ⁴ described a classification with 4 categories: (1) chronic hypertension, (2) preeclampsia‐eclampsia, (3) preeclampsia superimposed on chronic hypertension, and (4) gestational hypertension: (a) transient hypertension of pregnancy if preeclampsia is not present at the time of delivery and BP returns to normal by 12 weeks postpartum (a retrospective diagnosis) or (b) chronic hypertension if the elevation persists.

Hypertension diagnosed by BPs ≥140 mm Hg systolic and/or ≥90 mm Hg diastolic before pregnancy or during pregnancy before the 20th week of gestation is defined as chronic.

Though this patient had severe chronic hypertension of pregnancy, the clinicians following her had to assess the possibility of hypertension due to a secondary etiology and perform frequent assessments to rule out superimposed preeclampsia. The patient's young age and uncontrolled BP despite 4 drugs made her a candidate for secondary hypertension, but this workup was negative. The elevated renin and aldosterone levels seen in this case are typical of the hormonal changes occurring in normal pregnancy. ⁵

How is superimposed preeclampsia diagnosed in a pregnant patient with severe chronic hypertension? Diagnosis of superimposed preeclampsia is key because the patient would require urgent IV antihypertensive therapy with continuous fetal monitoring toward consideration of early delivery. The National High Blood Pressure in Pregnancy group states:

The diagnosis of superimposed preeclampsia is highly likely with the following findings:

• •In women with hypertension and no proteinuria early in pregnancy (<20 weeks), new‐onset proteinuria, defined as the urinary excretion of ≥0.3 g protein in a 24‐hour specimen;
• •In women with hypertension and proteinuria before 20 weeks' gestation;
• •Sudden increase in proteinuria;
• •Sudden increase in BP in a woman whose hypertension has previously been well controlled;
• •Thrombocytopenia (platelet count <100,000 cells/mm³);
• •Increase in alanine aminotransferase or aspartate aminotransferase to abnormal levels. ⁴

Increasing the risks for this patient were the presence of risk factors for superimposed preeclampsia: (1) preeclampsia is seen in 25% of pregnant patients with chronic hypertension; (2) preeclampsia recurs in 40% of patients who have previously developed preeclampsia before gestational week 30; (3) recurrence is higher when preeclampsia occurs in a multiparous woman; (4) risk is increased when a multiparous woman conceives with a new father; ⁶ and (5) preeclampsia is more common in severe chronic hypertension of pregnancy, where severe is defined as >160/110 mm Hg. ⁷ Established risk factors for preeclampsia are listed in Table II. ⁸ Contrariwise, laboratory markers making superimposed preeclampsia unlikely for this patient were the low uric acid levels and serum creatinine levels appropriate for normal pregnancy ⁵ (Table III). Symptoms suggestive of preeclampsia, including headache, blurred vision, and right upper quadrant or epigastric pain, may be nonspecific but require an immediate laboratory investigation and possibly hospitalization for maternal and fetal monitoring. This patient had chronic headaches complicating this evaluation and refused several requests for hospitalization.

Table II.

Established Risk Factors for Preeclampsia

Primiparity

Prior personal or maternal history of preeclampsia

Obesity

Hypertension

Diabetes mellitus

Renal disease

Collagen vascular disease

Thrombophilia

Multiple gestation

Reprinted with permission from Solomon et al. 8

Table III.

Laboratory Indicators of Preeclampsia

Test	Rationale
Hemoglobin and hematocrit	Hemoconcentration supports diagnosis of preeclampsia and is an indicator of severity. Values may be decreased, however, if hemolysis accompanies the disease.
Platelet count	Thrombocytopenia suggests severe preeclampsia.
Quantification of protein excretion	Pregnancy hypertension with proteinuria should be considered preeclampsia (pure or superimposed) until it is proved otherwise.
Serum creatinine level	Abnormal or rising serum creatinine levels, especially in association with oliguria, suggest severe preeclampsia.
Serum uric acid level	Increased serum uric acid levels suggest the diagnosis of preeclampsia.
Serum transaminase levels	Rising serum transaminase values suggest severe preeclampsia with hepatic involvement.
Serum albumin, lactic acid	For women with severe disease, these values indicate the extent of endothelial leak (hypoalbuminemia), presence of hemolysis (lactic acid dehydrogenase level increase, schizocytosis, spherocytosis), and possible coagulopathy, including thrombocytopenia.
Reprinted with permission from the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. 4

What Drugs Are Safe to Treat Chronic Hypertension in a Pregnant Patient? On the basis of preserved uteroplacental blood flow and fetal hemodynamics, and a small follow‐up study of exposed infants followed for 7.5 years, ⁴ , ⁹ , ¹⁰ methyldopa is a preferred drug; however, the experience in nonpregnant individuals is that methyldopa can cause fluid retention and that monotherapy may not be effective or may even worsen hypertension. Though diuretic therapy for chronic hypertension may reduce the physiologic expansion of plasma volume that occurs in normal pregnancy, diuretics for chronic hypertension of pregnancy have not been associated with poor fetal outcomes and do prevent progression to more serious hypertension. The national working group concluded that diuretics “are safe and efficacious agents, can markedly potentiate the response to other antihypertensive agents, and are not contraindicated in pregnancy except in settings where uteroplacental perfusion is already reduced (preeclampsia and intrauterine growth restriction).” ⁴ This group advises the use of the same medication in pregnant hypertensives as in nonpregnant patients, except for the use of angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).

β‐blockers, in common with methyldopa and labetalol, blunt progression to more severe hypertension (defined as BPs >160/110 mm Hg). ¹¹ In fact, the blunting of progression to more severe hypertension is the only consistent benefit seen in the clinical trials of drug treatment of chronic hypertension in pregnancy. A small, prospective, randomized, double‐blind, placebo‐controlled trial ¹² and a retrospective study, ¹² however, showed significantly reduced birth weights using atenolol. Other β‐blockers such as metoprolol, labetalol, pindolol, and oxyprenalol ¹¹ , ¹³ , ¹⁴ prevent progression of hypertension without fetal growth retardation. Though being small for gestational age at birth due to hypertension has been associated with lower development scores, studies have not looked at development scores for children exposed to individual antihypertensive agents ¹⁵ other than methyldopa. ¹⁰

Calcium channel blockers (CCBs) have been used safely in pregnancy and may be more effective than β‐blockers. ¹¹ Reports have described the usage of verapamil, nifedipine, isradipine, nimodipine, nicardipine, and amlodipine. ¹⁴ Most of the described CCB usage has occurred later in pregnancy, though there have been no reports of increased teratogenicity due to first‐trimester exposure. ⁶ CCBs can be synergistic with magnesium sulfate, predisposing to hypotension when used concurrently. ¹⁴ Because of reports of the successful use of combined dihydropyridine‐nondihydropyridine CCBs in refractory hypertension in non‐pregnant patients, ¹⁶ , ¹⁷ combination therapy with amlodipine and long‐acting diltiazem was used in this patient safely, but without success.

Clonidine and hydralazine have been used in studies of chronic hypertension in pregnancy. ⁹ ACEIs and ARBs are contraindicated in pregnancy due to associated oligohydramnios, neonatal renal failure, neonatal death, and possible major malformations of the cardiovascular and central nervous systems when exposed to ACE inhibitors in the first trimester. ¹⁸ , Table IV is a list from the Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ¹⁹ of drugs commonly used to treat chronic hypertension in pregnancy.

Table IV.

Drug Treatment of Chronic Hypertension in Pregnancy

Agent	Comments
Methyldopa	Preferred on the basis of long‐term follow‐up studies supporting safety
β‐Blockers	Reports of intrauterine growth retardation (atenolol), generally safe
Labetalol	Increasingly preferred to methyldopa because of reduced side effects
Clonidine	Limited data
Calcium antagonists	Limited data; no increase in major teratogenicity with exposure
Diuretics	Not initial agents; probably safe
ACEIs, angiotensin II receptor antagonists	Contraindicated; reported fetal toxicity and death
Reprinted with permission from the Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 19

What Outcomes Are Expected With Severe Chronic Hypertension of Pregnancy? Two studies have described experience managing pregnancy with severe chronic hypertension, defined as BP ≥160/110 mm Hg, ⁷ and ≥170/110 mm Hg. ²⁰ Vigil‐De Gracia et al ⁷ did not mention specific antihypertensive drugs, and Sibai and Anderson ²⁰ described the use of methyldopa and hydralazine. It is unlikely that diuretics were used consistently as adjunctive therapy in these studies. Sibai and Anderson observed no maternal deaths, but hospitalizations were frequently necessary for administration of parenteral medications. ²⁰ One patient required nitroprusside for hypertensive encephalopathy. Twenty patients (45%) suffered deterioration of renal function, but 15 of the 20 had superimposed preeclampsia, and renal function returned to baseline following delivery in 19. Twenty‐three patients (52%) developed preeclampsia. The second study reported findings in 154 women with chronic hypertension and BPs ≥160/110 mm Hg, representing 26% of pregnant women with hypertension and 0.6% of the 26,825 pregnancies surveyed. ⁷ Although 78 % experienced superimposed preeclampsia, there were no maternal deaths, and few of the 17% with major clinical complications had significant clinical impact (Table V).

Table V.

Maternal Outcomes With Chronic Severe Hypertension, >160/110 mm Hg (N=154)

Preeclampsia	120 (78)
HELLP syndrome*	13 (8.4)
Placental abruption	13 (8.4)
Acute renal insufficiency	6 (3.9)
Hypertensive encephalopathy	2 (1.3)
Pulmonary edema	2 (2.3)
Heart failure	1 (0.06)
Data are presented as number (percentage). *HELLP indicates hemolysis, elevated serum liver enzymes, low platelet count. Reproduced with permission from Vigil‐De Gracia et al. 7

Therefore, women with chronic hypertension of pregnancy under careful and frequent monitoring generally should expect good outcomes ⁸ even when the chronic hypertension is categorized as severe. ⁷ , ²⁰ Nonetheless, severe chronic hypertension of pregnancy is associated with fetal complications, notably smallness for gestational age and prematurity, as well as perinatal mortality. ²¹ When chronic hypertension of pregnancy is complicated by preeclampsia, the fetal consequences are more severe. ⁸ , ²⁰ , ²¹ , Table VI illustrates the incidence of perinatal mortality and smallness for gestational age in 2 studies. Outcomes in Sibai and Anderson ²⁰ are worse because this study examined preeclampsia complicating severe chronic hypertension, compared with preeclampsia complicating nonsevere chronic hypertension in McCowan et al. ²¹ While the only consistent benefit of the treatment of chronic hypertension in pregnancy is to prevent more severe hypertension, and possibly long‐term vascular damage, such treatment has not been found to reduce the risk of superimposed preecclampsia. ⁸

Table VI.

Studies Examining Fetal Outcomes of Chronic Hypertension in Pregnancy With and Without Preeclampsia

Study Data	Without Preeclampsia	With Preeclampsia
Number of patients
Sibai and Anderson 20	21	23
McCowan et al 21	129	26
Maternal age, mean ± SD, y
Sibai and Anderson 20	29.4±7.0	27.8±6.2
McCowan et al 21	31.7±5.3	32.7±6.9
Small for gestational age, %
Sibai and Anderson 20	5	78
McCowan et al 21	10.9	19.2
Perinatal mortality, %
Sibai and Anderson 20	0	48
McCowan et al 21	1.6	8.0

What Are the Indications and Considerations for Early Delivery? Indications for delivery in preeclampsia described in the National High Blood Pressure in Pregnancy report ⁶ (Table VII) are associated with: (1) indicators of severe preecclampsia (thrombocytopenia, progressive hepatic dysfunction, progressive renal dysfunction); (2) severity of maternal symptoms (headaches, visual change, epigastric pain, vomiting); (3) indicators of fetal compromise (fetal growth restriction, oligohydramnios, suspected abruptio placentae, and nonreassuring fetal testing); and (4) gestational age ≥38 weeks.

Table VII.

Indications for Delivery in Preeclampsia

Maternal

Gestational age ≥38 wk*

Platelet count <100,000 cells/mm3

Progressive deterioration in hepatic function

Progressive deterioration in renal function

Suspected abruptio placentae

Persistent severe headaches or visual changes

Persistent severe epigastric pain, nausea, or vomiting

Fetal

Severe fetal growth restriction

Nonreassuring fetal test results

Oligohydramnios

*Delivery should be based on maternal and fetal conditions as well as on gestational age. Reprinted with permission from the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. 6

The severity and lack of control of hypertension in this case discussion patient was compounded by worrisome compliance issues and recent sign‐outs from the hospital against medical advice. The patient consistently refused further advances in her antihypertensive drugs, and also refused to enter the hospital for parenteral therapy when clinic BPs were as high as 196/134 mm Hg. Medication compliance could not be completely ascertained. Despite aggressive counseling regarding birth control, the patient had a positive pregnancy test 6 weeks following this delivery.